Metalloproteinases, including matrix metalloproteinases and aggrecanases, are known to have a role in the breakdown of connective tissue. Matrix metalloproteinases (“MMPs”) constitute a superfamily of proteolytic enzymes that are genetically related and capable of degrading almost all the constituents of extracellular matrix and basement membrane that restrict cell movement. Aggrecanases, members of the ADAMTS (A disintegrin and metalloproteinase with thrombospondin motifs) family of proteins, cleave aggrecan, a cartilage component also known as the large aggregating chondroitin sulphate proteoglycan.
MMPs and aggrecanases can degrade various components of connective tissue, including collagen and proteoglycan. In the absence of natural checks on this activity, a variety of pathologies and undesirable effects can occur. In fact, MMPs and aggrecanases are known to play a role in many disorders in which extracellular protein degradation/destruction occurs, such as cancer, osteoarthritis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (“COPD”), atherosclerosis, age-related macular degeneration, myocardial infarction, corneal ulceration and other ocular surface diseases, hepatitis, aortic aneurysms, tendonitis, central nervous system diseases, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft versus host disease, diabetes, inflammatory bowel disease, shock, invertebral disc degeneration, stroke, osteopenia, and periodontal diseases.
Therefore, metalloproteinase inhibitors are needed, including inhibitors of MMPs and aggrecanases. Additionally, selective inhibitors directed to specific MMPs and aggrecanases are valuable to avoid potential side effects.